Project Summary Deep venous thrombosis (DVT) and secondary pulmonary embolism (PE) affect 0.1-0.2% of the population and cause approximately 100,000 deaths annually in the US. Immobility and lack of muscular activity is the primary risk factor for DVT, an effect attributed to reduced venous flow. Autopsy studies have identified the venous valve sinus in the leg as the site of origin for DVT, but a molecular and cellular mechanism for this observation has not been identified. Present therapies for DVT include systemic anticoagulation pneumatic compression devices designed to augment venous flow. Our recent studies reveal that oscillatory shear forces generated in the venous valve sinus by muscular activity are required to stimulated a powerful anti-thrombotic endothelial phenotype that prevents venous thrombosis. Consistent with this mechanism, analysis of venous valves harvested at autopsy from individuals who died of DVT and fatal PE reveals reversal of the anti-thrombotic phenotype in the peri-valvular endothelium. These studies provide a hemodynamic, cellular and molecular mechanism for DVT that explains its association with immobility and site of origin at the venous valve sinus, and suggests that a mechanical device that restored peri-valvular oscillatory flow in high-risk patients would effectively prevent DVT by maintaining the natural anti-thrombotic phenotype at that site. Analysis of existing pneumatic devices reveals that they do not drive oscillatory flow at the venous valve sinus of the leg. Based on physiologic studies performed with human volunteers, we have designed and created a prototype device (termed ?Osciflex?) designed to restore oscillatory flow at the venous valves by mimicking the response to active toe curling. The Osciflex device simultaneously flexes and compresses the foot, an action that generates a high degree of oscillatory flow when performed manually. The goal of this proposal is to perform initial testing and design optimization of the Osciflex prototype in preparation for the creation of final devices to be used for a larger scale clinical trial. In Aim 1 we will test that ability of newly developed prototype Osciflex devices to drive oscillatory flow in the venous valve sinus in the legs of normal volunteers. In Aim 2 we will use these data to refine and improve the function of Osciflex to more effectively protect immobile individuals who are at high risk for DVT. If successful, the Osciflex device represents a novel means of effectively preventing DVT and PE in high-risk patients without an increased risk of bleeding.